作者
Man‐Fung Yuen,Tarik Asselah,Ira M. Jacobson,Maurizia Rossana Brunetto,Harry L.A. Janssen,Tetsuo Takehara,Jin Hou,Thomas N. Kakuda,Tom Lambrecht,Maria Beumont,Ronald Kalmeijer,Carine Guinard‐Azadian,Cristiana Mayer,John Jezorwski,Thierry Verbinnen,Oliver Lenz,Umesh Shukla,Michael Biermer,Stefan Bourgeois,Thomas Vanwolleghem,Frederik Nevens,Yves Horsmans,Hans Van Vlierberghe,Ana Catharina de Seixas Santos Nastri,Marcus Lacerda,Alnoor Ramji,Kathy Petoumenos,Carla S. Coffin,Harry L.A. Janssen,Scott Fung,Stephen Ryder,Jin Hou,Jan Šperl,Petr Urbánek,Stanislav Plíšek,Václav Hejda,Didier Samuel,Karine Lacombe,Fabien Zoulim,Dominique Guyader,F. Raffi,Tarik Asselah,Marc Bourlière,Marie‐Noëlle Hilleret,Heiner Wedemeyer,Julian Schulze zur Wiesch,Kathrin Sprinzl,Florian van Bömmel,Gudrun Hilgard,Michael Sabranski,Keikawus Arastéh,Henry LY Chan,Man‐Fung Yuen,Vincent Wai‐Sun Wong,Maurizia Rossana Brunetto,Gloria Taliani,Pietro Andreoné,Pietro Lampertico,Masayuki Kurosaki,Hiroshi Yatsuhashi,Kei Fujiwara,Tetsuo Takehara,Tomokazu Kawaoka,Yasuhiro Asahina,Hirayuki Enomoto,Kazuhisa Yabushita,Kazuo Notsumata,Koichi Takaguchi,Naoto Kawabe,Naoya Kato,Koji Ogawa,Tadashi Namisaki,Yoshiyuki Suzuki,Jung‐Hwan Yoon,Sang Hoon Ahn,Young‐Suk Lim,Seung Woon Paik,Kuang Kiat Kiew,Rosmawati Mohamed,Soek Siam Tan,Yeong Yeh Lee,Maria Hlebowicz,Hanna Berak,Jacek Gąsiorowski,Waldemar Halota,Ewa Janczewska,Natalia Geyvandova,Viacheslav Morozov,А А Андреева,Д. А. Гусев,E. I. Bessonova,М. Ф. Осипенко,Svetlana Romanova,Natalia Gankina,Olga Sagalova,Т. В. Степанова,Javier Crespo,M. Diago,Fernandez Inmaculada,José Luís Calleja,Xavier Forns,Marı́a Buti,Pisit Tangkijvanich,Tawesak Tanwandee,Teerha Piratvisuth,Apinya Leerapun,Gürdal Yılmaz,Fehmı Tabak,Ulus Salih Akarca,Murat Akova,Ramazan İdilman,Daniel Forton,David Bell,Kosh Agarwal,Patrick Kennedy,Franco Felizarta,Mark Sulkowski,Ronald Nahass,Sergio Rojter,Ira M. Jacobson,Kevin Korenblat,Norman Gitlin
摘要
JNJ-73763989 (JNJ-3989), a small interfering RNA, targets all hepatitis B virus (HBV) RNAs, reducing all HBV proteins. JNJ-56136379 (JNJ-6379; also known as bersacapavir), a capsid assembly modulator, inhibits HBV replication. We aimed to evaluate the efficacy (ie, antiviral activity) and safety of these therapeutics in combination with nucleos(t)ide analogues in patients with chronic hepatitis B.The REEF-1 multicentre, double-blind, active-controlled, randomised, phase 2b study was done at 108 hospitals or outpatient centres across 19 countries in Asia, Europe, and North and South America. We included patients aged 18-65 years with chronic hepatitis B (defined as HBsAg positivity at screening and at least 6 months before screening or alternative markers of chronicity [eg, HBV DNA]), including those not currently treated, virologically suppressed, HBeAg positive, and HBeAg negative. Patients were randomly assigned (1:1:2:2:2:2) via permuted block randomisation according to a computer-generated schedule to receive oral nucleos(t)ide analogues once per day plus placebo (control group); oral JNJ-6379 250 mg daily plus nucleos(t)ide analogues (JNJ-6379 dual group); nucleos(t)ide analogues plus subcutaneously injected JNJ-3989 at doses of 40 mg (JNJ-3989 dual 40 mg group), 100 mg (JNJ-3989 dual 100 mg group), or 200 mg (JNJ-3989 dual 200 mg group) every 4 weeks; or JNJ-6379 250 mg plus JNJ-3989 100 mg every 4 weeks plus nucleos(t)ide analogues (triple group) for 48 weeks followed by a follow-up phase. An interactive web response system provided concealed treatment allocation, and investigators remained masked to the intervention groups until the primary analysis at week 48. The primary endpoint was the proportion of patients meeting predefined nucleos(t)ide analogue-stopping criteria (alanine aminotransferase <3 × upper limit of normal, HBV DNA below the lower limit of quantitation, HBeAg negative, and HBsAg <10 IU/mL) at week 48. All patients who received at least one dose of study drug were included in the analysis population used for primary efficacy assessment, excluding those who withdrew because of COVID-19-related reasons, withdrew before week 44, or had no efficacy data (ie, the modified intention-to-treat population). Safety was assessed in all participants who received at least one dose of study drugs. This trial is registered with ClinicalTrials.gov, NCT03982186. The study has been completed.Between Aug 1, 2019, and April 26, 2022, 470 patients (310 [66%] male and 244 [52%] White) were randomly assigned: 45 to the control group, 48 to the JNJ-6379 dual group, 93 to the JNJ-3989 dual 40 mg group, 93 to the JNJ-3989 dual 100 mg group, 96 to the JNJ-3989 dual 200 mg group, and 95 to the triple group. At week 48, five (5%; 90% CI 2-11) of 91 patients in the JNJ-3989 dual 40 mg group, 15 (16%; 10-24) of 92 in the JNJ-3989 dual 100 mg group, 18 (19%; 13-27) of 94 in the JNJ-3989 dual 200 mg group, eight (9%; 4-15) of 94 in the triple group, and one (2%; 0-10) of 45 in the control group met nucleos(t)ide analogue stopping criteria. No patients in the JNJ-6379 dual group met stopping criteria. 38 (81%) patients who met nucleos(t)ide analogue-stopping criteria at week 48 were virologically suppressed and HBeAg negative at baseline. Ten (2%) of 470 patients had serious adverse events during the treatment phase, and two patients (one each from the JNJ-3989 dual 200 mg group [exercise-related rhabdomyolysis] and the triple group [increase in ALT or AST]) had serious adverse events related to study treatment. During follow-up, 12 (3%) of 460 patients had a serious adverse event; one (<1%), a gastric ulcer, was considered to be related to nucleos(t)ide analogues and occurred in a patient from the JNJ-3989 dual 200 mg group. 29 (6%) of 460 patients in the treatment phase and in ten (2%) of 460 patients in the follow-up phase had grade 3 or 4 adverse events. Five (1%) of 470 patients discontinued treatment due to adverse events, and there were no deaths.Although treatment with JNJ-3989 led to a dose-dependent response for meeting nucleos(t)ide analogue-stopping criteria, it rarely led to HBsAg seroclearance. However, most patients treated with JNJ-3989 had clinically meaningful reductions in HBsAg that might contribute to a liver environment conducive to better immune control and, in turn, might improve the response to immune-modulating therapies.Janssen Research and Development.